ReFRAME
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ReFRAME
Posted on August 4th, 2020 by Dr. Francis Collins
Caption: Robotic technology screening existing drugs for new purposes. Credit: Scripps Research
https://directorsblog.nih.gov/tag/reframe/
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It usually takes more than a decade to develop a safe, effective anti-viral therapy. But, when it comes to coronavirus disease 2019 (COVID-19), we don’t have that kind of time. One way to speed the process may be to put some old drugs to work against this new disease threat. This is generally referred to as “drug repurposing.”
NIH has been doing everything possible to encourage screens of existing drugs that have been shown safe for human use. In a recent NIH-funded study in the journal Nature, researchers screened a chemical “library” that contained nearly 12,000 existing drug compounds for their potential activity against SARS-CoV-2, the novel coronavirus that causes COVID-19 [1]. The results? In tests in both non-human primate and human cell lines grown in laboratory conditions, 21 of these existing drugs showed potential for repurposing to thwart the novel coronavirus—13 of them at doses that likely could be safely given to people. The majority of these drugs have been tested in clinical trials for use in HIV, autoimmune diseases, osteoporosis, and other conditions.
These latest findings come from an international team led by Sumit Chanda, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. The researchers took advantage of a small-molecule drug library called ReFRAME [2], which was created in 2018 by Calibr, a non-profit drug discovery division of Scripps Research, La Jolla, CA.
In collaboration with Yuen Kwok-Yung’s team at the University of Hong Kong, the researchers first developed a high-throughput method that enabled them to screen rapidly each of the 11,987 drug compounds in the ReFRAME library for their potential to block SARS-CoV-2 in cells grown in the lab. The first round of testing narrowed the list of possible COVID-19 drugs to about 300. Next, using lower concentrations of the drugs in cells exposed to a second strain of SARS-CoV-2, they further narrowed the list to 100 compounds that could reliably limit growth of the coronavirus by at least 40 percent.
Generally speaking, an effective anti-viral drug is expected to show greater activity as its concentration is increased. So, Chanda’s team then tested those 100 drugs for evidence of such a dose-response relationship. Twenty-one of them passed this test. This group included remdesivir, a drug originally developed for Ebola virus disease and recently authorized by the U.S. Food and Drug Administration (FDA) for emergency use in the treatment of COVID-19. Remdesivir could now be considered a positive control.
These findings raised another intriguing question: Could any of the other drugs with a dose-response relationship work well in combination with remdesivir to block SARS-CoV-2 infection? Indeed, the researchers found that four of them could.
Further study showed that some of the most promising drugs on the list reduced the number of SARS-CoV-2 infected cells by 65 to 85 percent. The most potent of these was apilimod, a drug that has been evaluated in clinical trials for treating Crohn’s disease, rheumatoid arthritis, and other autoimmune conditions. Apilimod is now being evaluated in the clinic for its ability to prevent the progression of COVID-19. Another potential antiviral to emerge from the study is clofazimine, a 70-year old FDA-approved drug that is on the World Health Organization’s list of essential medicines for the treatment of leprosy.
Overall, the findings suggest that there may be quite a few existing drugs and/or experimental drugs fairly far along in the development pipeline that have potential to be repurposed for treating COVID-19. What’s more, some of them might also work well in combination with remdesivir, or perhaps other drugs, as treatment “cocktails,” such as those used to successfully treat HIV and hepatitis C.
This is just one of a wide variety of drug screening efforts that are underway, using different libraries and different assays to detect activity against SARS-CoV-2. The NIH’s National Center for Advancing Translational Sciences has established an open data portal to collect all of these data as quickly and openly as possible. As NIH continues its efforts to use the power of science to end the COVID-19 pandemic, it is critically important that we explore as many avenues as possible for developing diagnostics, treatments, and vaccines.
References:
[1] Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Riva L, Yuan S, Yin X, et al. Nature. 2020 Jul 24 [published online ahead of print]
[2] The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Janes J, Young ME, Chen E, et al. Proc Natl Acad Sci USA. 2018;115(42):10750-10755.
Links:
Coronavirus (COVID-19) (NIH)
ReFRAMEdb (Scripps Research, La Jolla, CA)
The Chanda Lab (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA)
Yuen Kwok-Yung (University of Hong Kong)
OpenData|Covid-19 (National Center for Advancing Translational Sciences/NIH)
Scripps Research scientists leveraging ReFRAME drug repurposing collection against COVID-19 coronavirus epidemic
Ongoing efforts to identify medicines that could be rapidly repurposed against coronavirus.
March 18, 2020
2020-03-18-scripps-edu-news-press-reframe-drug-repurposing-covid19.pdf
2020-03-18-scripps-edu-news-press-reframe-drug-repurposing-covid19-img-1.jp
Scripps Research teams are looking for anti-viral drugs that could be given to people already exposed to the novel coronavirus causing the COVID-19 pandemic. One priority is to test already approved drugs, or drugs with significant safety data in humans available, for activity against the novel coronavirus, known as SARS-CoV-2. These drugs could be made available to treat coronavirus patients on a much quicker timescale than novel therapies.
Calibr, the drug development division of Scripps Research, is leveraging a unique resource—the ReFRAME drug repurposing collection. With support from the Bill & Melinda Gates Foundation, Calibr compiled ReFRAME, the world’s leading collection of known drugs, comprising over 14,000 compounds that have been approved by the FDA for other diseases or have been extensively tested for human safety. Calibr also developed an open source database containing preclinical and clinical data on these compounds. Since information on the drugs’ therapeutic properties and safety is known, they can be screened and rapidly advanced into the clinic.
Since its creation in 2018, ReFRAME has been distributed broadly to nonprofit collaborators for global health and used to identify repurposing opportunities for a range of diseases. When the COVID-19 outbreak began, Calibr was able to mobilize ReFRAME quickly to begin searching for existing drugs and other compounds that might be repurposed against the coronavirus.
Previous studies showed that some of these molecules appear effective against closely related SARS and MERS coronaviruses, and now the teams are working together to test those same compounds against the novel SARS-CoV-2 virus. They are also screening for compounds in ReFRAME that prevent the virus from infecting cells in the first place.
In a separate project, Calibr scientists are collaborating with the Scripps Research lab of Dennis Burton, PhD, to screen for molecules that prevent SARS-CoV-2 from replicating after it enters cells. They hope that such a compound could serve as the basis for an antiviral therapy.
Calibr scientists are also screening for drugs that could augment the effectiveness of the Gilead drug remedesivir which is currently being tested in five COVID-19 clinical trials, as well as partnering with pharma companies to screen earlier stage antiviral drugs.
Since the outbreak began, Calibr has established collaborations to screen the ReFRAME library for potential coronavirus therapies with nine outside research teams, including US laboratories in Maryland, Massachusetts, New York, and Texas, as well as overseas labs in the UK, Germany, Belgium and Hong Kong. ReFRAME has been highlighted in the COVID-19 Therapeutics Acceleratorlaunched by the Bill & Melinda Gates Foundation. Together, Calibr and the Gates Foundation are working to establish collaborations with the leading pharma companies to augment ReFRAME’s collection of antiviral compounds for future pandemic response.
Researchers Hunting For Existing Drugs to Repurpose in Fight Against COVID-19
Thursday, April 2, 2020
Photo courtesy of Scripps Research. Scientists at Scripps Research’s drug development arm, Calibr, work with a drug repurposing library that contains more than 14,000 compounds known to be safe in humans. Calibr is tapping into this collection to find antiviral drugs for those who’ve been exposed to the novel coronavirus.
https://www.sdbj.com/news/2020/apr/02/researchers-hunting-existing-drugs-repurpose-fight/
2020-04-02-san-diego-business-journal-researchers-hunting-existing-drugs-repurpose-fight.pdf
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San Diego researchers are hunting for existing drugs that could be repurposed to fight COVID-19.
The idea is that already-proven drugs could be a quicker way to treat the novel coronavirus compared to medicines that were only recently hatched.
Existing Drugs
To find promising programs, Calibr — the drug development division of Scripps Research — turned to ReFrame, a drug database that it compiled. ReFrame encompasses 14,000 compounds that received U.S. Food and Drug Administration approval or that are far along in clinical testing.
Calibr has also developed an open source database containing pre-clinical and clinical data on these compounds.
“When the COVID-19 outbreak began, Calibr was able to mobilize ReFRAME quickly to begin searching for existing drugs and other compounds that might be repurposed against the coronavirus,” Scripps said in a news release.
Calibr’s work also includes analyzing existing drugs that could potentially complement a drug from Foster City, Calif.-based Gilead called remedesivir.
Remedesivir is being studied as a potential coronavirus treatment in five clinical trials, with some results due out in April.
Nine Teams
Since the outbreak started, nine research teams have tapped ReFrame, including U.S. laboratories in Maryland, Massachusetts, New York, and Texas, as well as international labs in the UK, Germany, Belgium and Hong Kong.
Among those using ReFrame is Sanford Burnham Prebys Medical Discovery Institute in La Jolla.
Sumit Chanda, director of the institute’s Immunity and Pathogenesis Program, is leading a team that’s screening compounds in the database.
“He will share his findings publicly as they are important for the scientific and medical community,” an institute spokeswoman said in an email.
The ReFrame project is supported by a $50 million grant Calibr received earlier this year from the Bill & Melinda Gates Foundation. The grant will also push forward potential therapies for tuberculosis and malaria, new contraceptives and gut health
Since 2014, the foundation has pledged $135 million to Scripps Research.